Adriamycin has been suspected of causing experimental nephrotoxicity. We report here that adriamycin induces a nephrotic syndrome in rats, proteinuria beginning 4 to 5 days after a single intravenous injection (7.5 mg. per kg. of body weight). The full expression of the syndrome develops 13 to 15 days later. Minimal alterations at light microscopy, negative immunofluorescence, and only some focal "fusion" of foot processes can be observed by electron microscopy in the early phase after injection (28 hours). At 13 days, loss of foot process architecture, and replacement by flattened epithelial cytoplasm, was invariably found. These ultrastructural findings became extensive at 28 days follow-up. Colloidal iron staining of kidney biopsies revealed loss of glomerular polyanions as early as 3 hours and very marked loss at 28 hours after adriamycin injection. Polyanions were totally absent at 13 days and were still undetectable at 28 days. Thus, the loss of polyanionic charges associated with the sialic acid coat precedes the ultrastructural changes and the onset of proteinuria. These changes appeared similar to those reported in rats treated with daunomycin or puromycin animonucleoside. The present study supports in a different animal model the concept that both morphologic changes and proteinuria are the consequence of a common primary event that is the loss of glomerular fixed negative charges.